Synthesis of new indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones as potential antitumor agents

Article abstract of DOI:10.1016/j.bmc.2008.08.023

Novel racemic indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones 3-29 were obtained regioselectivily from the reaction of 5,6-diamino-3,4-dihydropyrimidin-4-ones 1 and 2-arylideneindandiones 2 as reagents. These compounds have been evaluated at the US

Full text of DOI:10.1016/j.bmc.2008.08.023

Bioorganic & Medicinal Chemistry 16 (2008) 8492–8500
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of new indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones
as potential antitumor agents
a
a
a
a
b
Braulio Insuasty a, , Fabian Orozco , Carolina Lizarazo , Jairo Quiroga , Rodrigo Abonia , Mike Hursthouse ,
*
Manuel Nogueras c, Justo Cobo c
a Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A.A. 25360 Cali, Colombia
b School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
c Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel racemic indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones 3–29 were obtained regioselecti-
vily from the reaction of 5,6-diamino-3,4-dihydropyrimidin-4-ones 1 and 2-arylideneindandiones 2 as
reagents. These compounds have been evaluated at the US National Cancer Institute (NCI) for their ability
to inhibit approximately 60 different human tumor cell lines, where 5 and 6 presented remarkable activ-
ity against 57 and 48 cancer cell lines, respectively, with the most important GI50 values ranging from
Received 1 July 2008
Revised 5 August 2008
Accepted 6 August 2008
Available online 12 August 2008
0.49 to 1.46 lM, in vitro assay.
Keywords:
Ó 2008 Published by Elsevier Ltd.
Regioselective cyclocondensation
5,6-Diamino-3,4-dihydropyrimidin-4-ones
2-Arylideneindandiones
Indenopyrimido[4,5-b][1,4]diazepine
Antitumoral
1. Introduction
cytotoxic activities of 6-aryl-6,7,10,12-tetrahydroindeno[1,2-
e]pyrimido[4,5-b][1,4]diazepine-5,11-diones 3–29.
The 1,4-diazepine system is considered today a relevant phar-
macophore in a wide range of biological activities, with special
examples in the well-known benzodiazepines extensively studied
synthetically and pharmacologically.1,2 Recently, the syntheses of
analogues possessing heterocycles or even more complex fused
systems such as a pyrimidine ring attracted attention since they
showed to be promising pharmacophores,3–5 and some of them
found to be specially active against different cancer types, as de-
scribed in one of our previous papers.6
The compounds were evaluated for their antitumoral activity
against approximately 60 different human tumor cell lines, repre-
senting leukemia, melanoma, and cancers of the lung, colon, brain,
ovary, breast, prostate, and kidney.
2. Results and discussion
2.1. Chemistry
On the other hand, previous works have shown that fusing an
indeno moiety to the main core could enhance the pharmacologic
potential of a target molecule, there have been found derivatives
with 1,3-indandione moiety as potential drugs in a wide range of
bioactivities including antioxidants,7 anticoagulants,8 antibacteri-
als,9–12 and CDK (Cyclin-Dependent Kinases) inhibitors.13,14 Con-
sidering this information, the fusion of pyrimidodiazepine core
and indeno moiety becomes an interesting synthetic strategy to
search pharmacologically target molecules.
Heating of 5,6-diamino-2-methylthiopyrimidin-4(3H)-one (1a)
or 5,6-diamino-2-methoxypyrimidin-4(3H)-one (1b) or the corre-
sponding 3-methyl derivatives of both (1c,d) with equimolar quan-
tities of 2-arylideneindandiones 2a–h in ethanol in the presence of
catalytic amounts of acetic acid afforded the desired structures 3–
29 in good yields (see Scheme 1).
The synthesis of all compounds proceeded regioselectively, and
most of the derivatives were obtained as amorphous solids with
the exception of compounds 4, 22, and 27b, isolated as crystals
suitable for X-ray diffraction analysis, which, combined with
NMR studies and elemental analysis provided the full characteriza-
tion of such compounds.
In this work, targeting the preparation of such indeno fused bio-
active heterocycles, we report the regioselective synthesis and
In the X-ray crystal structures of compounds 4 and 22 (struc-
tures (A) and (B) in Figure 1, respectively), 1,4-diazepine ring
exhibits a boat-like conformation with the aryl ring out of the
* Corresponding author. Tel.: +57 2 3393248; fax: +57 2 33392440.
E-mail address: brainsu@univalle.edu.co (B. Insuasty).
0968-0896/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2008.08.023

B. Insuasty et al. / Bioorg. Med. Chem. 16 (2008) 8492–8500
8493
1
O
O
N
H
R1
R2
R1
R2
NH2
NH2
R3
EtOH/AcOH
reflux
N
O
12
11
N
N
5
+
5a
7
O
N
N
H
6
R3
a NO2 e H
b Cl f Me
c Br g MeO
d F
R1
R2
O
a H SMe
b H OMe
c Me SMe
d Me OMe
3-29 60-74%
1
2
R3
h CF3
Compound
R1
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
R2
R3
Cl
Br
F
H
CH3
OCH3
CF3
NO2
Cl
Br
H
CH3
OCH3
NO2
Compound
R1
R2
R3
Cl
Br
F
H
CH3
OCH3
CF3
NO2
Cl
3
4
5
6
7
8
9
10
11
12
13
14
15
16
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
SCH3
17
18
19
20
21
22
23
24
25
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
26
27a,b
28
Br
H
CH3
OCH3
29
Scheme 1. Synthesis of novel Indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones 3–29.
Figure 1. ORTEP drawing of compound 4ꢀꢀꢀDMF (A) and 22 (B).
plane. Such a conformation is slightly distorted by the fused indeno
moiety, but according to the expected behavior of 1,4-diazepine
ring as reported in some studies.15,16
In the particular case of compound 27a, an additional unex-
pected product (denoted as 27b) was isolated in a moderate yield
compared to the main product (see Scheme 2), and was character-
ized as a 5a-hydroxy derivative formed probably from compound
27a by protonation of the carbonyl oxygen belonging to the indeno
moiety, followed by addition of a water molecule to C-5a. Then,
tautomerization of carbonyl group and addition of a proton to C-
12a with further oxidation generated the C@N group, yielded the
structure 27b.
The structure of derivative 27b was unambiguously determined
by X-ray diffraction analysis (see Fig. 2).
The X-ray crystal structure of derivative 27b (Fig. 2) shows that
the introduction of the hydroxyl group caused an inversion of the
aryl group in the conformation described above for compounds 4
and 22. In this particular case, the boat-like conformation remains
but is more pronounced with the aryl ring entering the plane and
the hydroxyl group out of the plane. This fact could be expected,
O
N
O
N
O
H
N
O
N
H3C
H3C
H3C
NH2
NH2
EtOH/AcOH
reflux
N
N
N
+
+
O
O
OH
H3CO
H3CO
H3CO
N
N
H
N
H
O
1d
2e
27a 67%
27b 25%
Scheme 2. Synthesis of compound 27 and the hydroxy derivative 27b.

8494
B. Insuasty et al. / Bioorg. Med. Chem. 16 (2008) 8492–8500
2.2. Anticancer activity
The two-stage screening process started with the evaluation of
seven compounds (5, 6, 8, 20, 22, 27, and 29) selected by NCI,
against the 60 cell lines at a single dose of 1.0 M. The output from
l
the single dose screen was reported as a mean graph available for
analysis by the COMPARE program. The results of the primary as-
say showed that compounds 8, 20, 22, 27, and 29 were essentially
inactive, while compounds 5 and 6 were active (Table 1).
Therefore, a secondary screening was performed, in order to
determine their cytostatic activity, against the 60 cell lines panel
representing leukemia, melanoma, and cancers of lung, colon, brain,
ovary, breast, prostate, and kidney. The compounds were evaluated
at five concentration levels (100, 10, 1.0, 0.1, and 0.01 lM). The test
consisted of a 48 h continuous drug exposure protocol using sul-
forhodamide B (SRB) protein assay to estimate cell growth. Details
of this evaluation method, and the complementary information re-
lated with the activity pattern over all cell lines, have been pub-
lished.20–22 Table 2 showed that compound 5 displayed the most
remarkable activity against 57 human tumor cell lines, SNB-75
(CNS) and MDA-MB-435 (breast cancer) being the most sensitive
Figure 2. ORTEP drawing of compound 27bꢀꢀꢀH2O.
probably due to the difference in planarity of indeno moiety with
and without the ,b-unsaturation for the studied structures, as
a
well as its contribution to the conformation of the main diazepine
core.
The high regioselectivity observed in all the reactions could be
explained as a matter of the major nucleophilicity of the amino
group on C-5 of ortho-diamines 1, enhanced by the electronic effect
of the pyrimidine ring and the groups attached to it.17,18 Therefore,
condensation between such amino group and one of the carbonyl
groups of 2-arylideneindandiones 2 can be followed by a Michael’s
addition of the less nucleophilic amino group (amino group on C-6)
to the C@C double bond.
strains (GI50: 1.46 and 1.65 lM, respectively, and LC50 > 100 lM
for both). In a similar way to previous derivative, compound 6 (ac-
tive against 48 human tumor cell lines) was found especially effec-
tive against the cell line MDA-MB-435 of breast cancer panel
exhibiting a considerably better GI50 of 0.49
lM (LC50 > 100 lM),
as well as a GI50 of 1.41 M (LC50 > 100 M) for cell line NCI-
l
l
H522 of non-small cell lung cancer panel. In summary, derivatives
5 and 6 show significant activities (Table 2), with GI50 ranges from
The IR spectra for all products show typical bands between
3210 and 3381 cmꢁ1 (NH groups) and 1524–1690 cmꢁ1 (C@O,
C@N and C@C groups). Nitro-derivatives (10, 16, and 24), show
characteristic bands at 1338–1340 and 1521–1531 cmꢁ1 due to
NO2 asymmetric and symmetric stretching vibrations, respectively.
The structure elucidations of compounds 3–29 were based on
the spectral data (1H NMR, 13C NMR, and mass spectrometry) sum-
marized in the experimental section. In the 1H NMR spectra for all
compounds, there are three characteristic protons of the 1,4-diaze-
pine ring. Proton H-6 in the stereogenic center appears as a doublet
at d = 4.99–5.70 ppm with a coupling constant of 3J = 4.5–4.9 Hz
(except for the particularly high value of 27b with 3J = 6.6 Hz),
due to the vicinal position of proton NH-7 observed as a doublet
as well at d = 7.13–8.98 ppm, while proton NH-12 does not lead
to any coupling appearing as singlet at d = 7.93–10.54 ppm. Pyrim-
idine proton NH-10 of derivatives 3–15 is displayed as a singlet at
d = 9.95–12.78 ppm. Compound 27b presents the analogue signals
of diazepine ring, except for N-12 which in this case belongs to
C@N group and 5a-OH which appears as a singlet at d = 6.49 ppm.
Analysis of 13C, DEPT-135, and two-dimensional heteronuclear
NMR spectra provided the final structural elucidation of compounds
3–29. So, the signal for C-6 is in the range d 52.9–55.6 ppm, whereas
the signal of C-5a and C-12a is displayed at d 104.4–107.2 ppm and
d = 152.4–153.0 ppm, respectively. Quaternary carbon C-4a pre-
sents a peak at d 100.0–104.6 ppm while signals for C-9a are dis-
played between d 142.7–149.3 ppm. This great difference in the
chemical shifts of such carbons can be taken as a hint for a push–pull
substituted C@C double bond in structures 3–29.
1.46–49.3 lM and 0.49–22.0 lM, respectively; against other cell
lines from the different panels of cancer types and as discussed
above, they share activity against cell line MDA-MB-435 of breast
cancer panel. The cytotoxicities associated with compounds 5 and
6, and measured as LC50 goes from 35.1 lM to >100 lM, for all cell
lines, indicating a low toxicity of the title compounds for normal
human cell lines as required for potential antitumor agents.
3. Conclusion
Thesynthesisandcytotoxicactivityof novel6-aryl-6,7,10,12-tet-
rahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones
have been performed. Results showed that among the seven inden-
opyrimidodiazepines evaluated, derivatives 5 and 6 exhibited the
highest activities against different cancer cell lines with remarkable
values. These compounds could be lead compounds for synthesizing
new series of analogues of 1,4-diazepines with potential antitumor
activities.
4. Experimental
Melting points were determined in a Buchi Melting Point
Apparatus and are uncorrected. The 1H- and 13C NMR spectra
Table 1
Results of primary anticancer assay for seven compounds selected by the NCI
Finally, 13C NMR, DEPT-135, and two-dimensional heteronu-
clear NMR spectra provided the final structural elucidation of
derivatives 3–29. Mass spectra of all compounds exhibit well-de-
fined molecular ions with some particular fragmentation patterns
such as the loss of the fused indeno moiety (M+Å-128, M+Å-157),
CO (M+Å-28), aryl group, and Ar-C„N. The latter fragmentation oc-
curs by a cleavage on C–C bond in b position to diazepine NH (type-
B homolytic process) followed by a C–N scission (type-A5 hetero-
lytic process), which generates a constant and stable radical.19
Compound
Activitya
5
6
8
20
22
27a
29
A
A
NA
NA
NA
NA
NA
a
Activity denoted as: A = active; NA = not active.

B. Insuasty et al. / Bioorg. Med. Chem. 16 (2008) 8492–8500
8495
Table 2
In vitro testing results expressed as growth inhibition of cancer cell lines for compounds 5 and 6a
Compound
Number of cell lines
Most sensitive cell lines (GI50 < 20
lM)
b
c
Investigated
59
Giving positive GI50
Panel
Cell line
GI50
(
lM)
LC50 (lM)
b
GI50
(lM)
No
59
Range
5
1.46–49.3
Leukemia
CCRF-CEM
HL-60 (TB)
K-562
MOLT-4
RPMI-8226
SR
8.16
6.54
4.05
19.5
4.20
6.31
12.6
18.2
11.9
>100
>100
>100
>100
>100
>100
>100
>100
Non-small cell
Lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
SF-268
SF-295
95.6
>100
9.52
15.3
13.5
13.9
5.10
3.17
13.0
12.2
7.23
4.57
3.36
3.77
4.48
>100
>100
>100
>100
>100
>100
76.1
44.7
>100
35.1
39.5
>100
>100
>100
92.0
Colon cancer
CNS cancer
12.7
3.67
8.90
SF-539
SNB-19
SNB-75
U251
LOX IMVI
MALME-3M
M14
15.9
>100
>100
48.6
95.2
>100
>100
>100
>100
>100
>100
61.8
>100
95.6
95.2
>100
60.4
57.7
>100
>100
92.8
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
1.46
5.43
8.78
Melanoma
19.6
6.29
9.03
6.13
3.04
11.3
3.38
15.4
17.7
13.1
14.1
12.4
4.88
11.6
3.30
14.5
12.9
16.3
7.72
16.2
5.18
6.42
12.6
SK-MEL-28
SK-MEL-5
UACC-62
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
786-0
A498
ACHN
CAKI-1
RXF 393
TK-10
UO-31
PC-3
DU-145
MCF7
NCI/ADR-RES
MDA-MB-231/ATCC
HS 578T
MDA-MB-435
T-47D
Ovarian cancer
Renal cancer
Prostate cancer
Breast cancer
5.85
1.65
14.2
BT-549
8.50
6
59
56
0.49–22.0
Leukemia
CCRF-CEM
HL-60 (TB)
K-562
MOLT-4
RPMI-8226
SR
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
5.92
2.51
1.27
5.24
3.01
1.51
6.98
12.8
5.37
12.0
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
Non-small cell
Lung cancer
4.20
5.82
(continued on next page)

8496
B. Insuasty et al. / Bioorg. Med. Chem. 16 (2008) 8492–8500
Table 2 (continued)
Compound
Number of cell lines
Giving positive GI50
Most sensitive cell lines (GI50 < 20
l
M)
b
c
Investigated
Panel
Cell line
GI50
(
l
M)
LC50 (lM)
b
GI50
(
lM)
No
Range
NCI-H322M
NCI-H460
NCI-H522
COLO 205
HCC 2998
HCT-116
HCT-15
HT 29
KM 12
SW 620
SF-268
SF-295
SF-539
13.5
3.16
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
1.41
3.53
6.75
4.21
2.80
2.97
2.27
2.92
4.55
1.91
2.84
1.27
3.52
4.54
2.12
5.62
Colon cancer
CNS cancer
SNB-75
U251
Ovarian cancer
Renal cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-8
SK-OV-3
786-0
A498
ACHN
CAKI-1
SN12C
UO-31
PC
DU
MCF7
NCI/ADR-RES
MDA-MB-231/ATCC
HS 578T
MDA-MB-435
BT-549
46.4
>100
19.1
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
7.65
6.44
2.00
3.73
2.18
6.39
5.23
3.64
Prostate cancer
Breast cancer
13.4
2.40
4.54
4.09
2.10
0.49
5.35
4.61
T-47D
a
Data obtained from NCI’s in vitro disease-oriented human tumor cell lines screen.20–22
b
GI50 was the drug concentration resulting in a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug incubation.
Determined at five concentration levels (100, 10, 1.0, 0.1, and 0.01 M).
LC50 is a parameter of cytotoxicity and reflects the molar concentration needed to kill 50% of the cells.
l
c
were run on a Bruker Avance 400 spectrometer operating at
400 MHz and 100 MHz, respectively, using dimethyl sulfox-
ide-d6 as solvent and tetramethylsilane as internal standard.
The mass spectra were obtained on a Hewlett Packard HP En-
gine-5989 spectrometer (equipped with a direct inlet probe)
operating at 70 eV. The elemental analyses have been obtained
using a LECO CHNS-900 elemental analyzer.
4.1.1. 9-methylthio-6-(4-chlorophenyl)-6,7,10,12-tetrahydroin-
deno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (3)
The compound was obtained as a red powder in a yield of 74%;
mp 285–286 °C; FTIR (KBr)
m 3360 (NH); 1619 (C@O); 1565 (C@N
and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.45 (s, 3H,
;
SCH3), 5.38 (d, 2H, H-6, J = 4.5 Hz), 7.21 (d, 2H, H-o, J = 8.5 Hz),
7.56 (d, 2H, H-m, J = 8.5 Hz), 7.29 (d, 1H, H-4, J = 7.0 Hz), 7.33 (t,
1H, H-3, J = 7.2 Hz), 7.40 (t, 1H, H-2, J = 6.8 Hz), 7.62 (d, 1H, H-1,
J = 7.3 Hz), 7.71 (d, 1H, H-7, J = 4.8 Hz), 7.93 (s, 1H, H-12) , 12.75
(s, 1H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6): d 13.1, 53.8,
102.0, 106.1, 118.1, 118.5, 120.6, 128.5, 128.8, 130.2, 131.5,
134.8, 137.8, 144.2, 148.9, 153.0, 154.3, 160.5, 188.5 ppm. MS
(70 eV) m/z (%): 422 (Mꢀ+, 100), 394 (17), 311 (21), 265 (58). Anal.
Calcd. For C21H15ClN4O2S: C, 59.64; H, 3.58; N, 13.15; S, 7.58.
Found: C, 59.57; H, 3.62; N, 13.19; S, 7.41
4.1. General Procedure for synthesis of 6-aryl-6,7,10,12-tetra-
hydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones
(3–29)
A mixture of 3.0 mmol of 1 (5,6-diamino-2-methylthiopyr-
imidin-4(3H)-one or 5,6-diamino-2-methoxypyrimidin-4(3H)-
one or 5,6-diamino-3-methyl-2-methylthiopyrimidin-4(3H)-one
or 5,6-diamino-3-methyl-2-methoxypyrimidin-4(3H)-one) and
3.0 mmol of 2-arylideneindandiones 2 was refluxed in 15 mL of
absolute ethanol and 1 mL of acetic acid for 6–8 h (TLC control).
4.1.2. 9-methylthio-6-(4-bromophenyl)-6,7,10,12-tetrahydroin-
deno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (4)
The compound was obtained as red crystals in a yield of 70%;
After cooling, the reaction mixture was neutralized with
a
solution of 10% NaHCO3 and cooled to 0 °C. The precipitate
formed overnight was filtered off and recrystallized from
dimethylformamide yielding compounds 4, 22, and 27b as
crystals and the remaining compounds as amorphous
solids.
mp 272–273 °C; FTIR (KBr)
m 3338 (NH); 1624 (C@O); 1571 (C@N
and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.46 (s, 3H,
;
SCH3), 5.37 (d, 2H, H-6, J = 4.6 Hz), 7.15 (d, 2H, H-o, J = 8.4 Hz),
7.30 (d, 1H, H-4, J = 7.0 Hz), 7.33 (t, 1H, H-3, J = 7.3 Hz), 7.39 (d,
2H, H-m, J = 8.4 Hz), 7.40 (t, 1H, H-2, J = 6.8 Hz), 7.61 (d, 1H, H-1,

B. Insuasty et al. / Bioorg. Med. Chem. 16 (2008) 8492–8500
8497
J = 7.3 Hz), 7.70 (d, 1H, H-7, J = 4.5 Hz), 7.93 (s, 1H, H-12), 12.78 (s,
1H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6): d 13.1, 53.9, 101.5,
106.1, 118.1, 120.2, 120.6, 128.9, 130.2, 131.5, 131.7, 134.8, 137.8,
144.7, 148.7, 153.0, 154.2, 159.2, 188.4 ppm. MS (70 eV) m/z (%):
468 (Mꢀ+, 100), 440 (12), 312 (19), 311 (72). Anal. Calcd. For
3H, SCH3), 3.47 (s, 3H, p-OCH3), 5.37 (d, 2H, H-6, J = 4.8 Hz), 7.01
(d, 2H, H-o, J = 8.5 Hz), 7.08 (d, 2H, H-m, J = 8.5 Hz), 7.29 (d, 1H,
H-4, J = 6.8 Hz), 7.32 (t, 1H, H-3, J = 7.0 Hz), 7.39 (t, 1H, H-2,
J = 7.3 Hz), 7.60 (d, 1H, H-1, J = 7.2 Hz), 7.65 (d, 1H, H-7,
J = 5.0 Hz), 8.65 (s, 1H, H-12), 12.70 (s, 1H, H-10) ppm; 13C NMR
(100 MHz, DMSO-d6): d 13.1, 54.2, 101.9, 106.9, 117.9, 120.5,
126.6, 129.4, 130.1, 131.5, 134.9, 136.3, 137.8, 142.3, 149.0,
152.9, 154.0, 159.2, 188.5 ppm. MS (70 eV) m/z (%): 418 (Mꢀ+,
100), 390 (9), 311 (16), 261 (83). Anal. Calcd. For C22H18N4O3S: C,
63.14; H, 4.34; N, 13.39; S, 7.66. Found: C, 63.10; H, 4.40; N,
13.31; S, 7.73.
C21H15BrN4O2S: C, 53.97; H, 3.24; N, 11.99; S, 6.86. Found: C,
54.01; H, 3.19; N, 12.03; S, 6.91.
Crystallographic data for 4 were collected at 120 K on a Bruker
Nonius Kappa Roper CCD area diffractometer using Mo-K
a X-ray
0
radiation (k = 0.71073 ÅA) and deposited at Cambridge Crystallo-
graphic data Center (CCDC reference: 692350).
4.1.3. 9-Methylthio-6-(4-fluorophenyl)-6,7,10,12-tetrahydroin-
deno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (5)
The compound was obtained as an orange powder in a yield of
4.1.7. 9-Methylthio-6-(4-trifluoromethylphenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (9)
68%; mp 245–246 °C; FTIR (KBr)
m
3353 (NH); 1618 (C@O); 1524
The compound was obtained as a dark-red powder in a yield of
(C@N and C@C) cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 2.94 (s, 3H,
SCH3), 5.36 (d, 2H, H-6, J = 4.6 Hz), 7.09 (d, 2H, H-o, J = 8.9 Hz), 7.61
(d, 2H, H-m, JF = 5.6 Hz, Jo–m = 8.9 Hz), 7.21 (d, 1H, H-4, J = 6.8 Hz),
7.35 (t, 1H, H-3, J = 7.4 Hz), 7.43 (t, 1H, H-2, J = 7.3 Hz), 7.74 (d, 1H,
H-1, J = 4.8 Hz), 7.75 (d, 1H, H-7, J = 7.2 Hz), 8.79 (s, 1H, H-12),
12.72 (s, 1H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6): d 12.6,
52.9, 101.3, 105.7, 135.5, 115.3, 118.3, 120.0, 128.0, 131.0, 131.7,
134.2, 137.8, 144.1, 148.4, 152.6, 153.6, 159.6, 187.7 ppm. MS
(70 eV) m/z (%): 406 (Mꢀ+, 100), 378 (11), 311 (16), 249 (92). Anal.
Calcd. For C21H15FN4O2S: C, 62.06; H, 3.72; N, 13.79; S, 7.89. Found:
C, 61.99; H, 3.79; N, 13.75; S, 7.78.
60%; mp 298–299 °C; FTIR (KBr)
m 3342 (NH); 1616 (C@O); 1581
(C@N and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.44 (s,
;
3H, SCH3), 5.39 (d, 2H, H-6, J = 4.6 Hz), 7.24 (d, 2H, H-m,
J = 8.3 Hz), 7.27 (d, 1H, H-4, J = 6.8 Hz), 7.33 (t, 1H, H-3,
J = 7.4 Hz), 7.38 (d, 2H, H-o, J = 8.3 Hz), 7.40 (t, 1H, H-2,
J = 7.2 Hz), 7.62 (d, 1H, H-1, J = 7.2 Hz), 7.74 (d, 1H, H-7,
J = 4.8 Hz), 8.85 (s, 1H, H-12), 12.65 (s, 1H, H-10) ppm; 13C NMR
(100 MHz, DMSO-d6): d 13.1, 54.0, 101.9, 105.6, 118.2, 120.6,
127.5, 128.1, 130.2, 131.5, 134.8, 137.9, 148.6, 150.0, 152.8,
154.2, 159.1, 188.3 ppm. MS (70 eV) m/z (%): 456 (Mꢀ+, 100), 428
(11), 311 (18), 299 (65). Anal. Calcd. For C22H15F3N4O2S: C, 57.89;
H, 3.31; N, 12.27; S, 7.03. Found: C, 57.95; H, 3.27; N, 12.22; S, 6.86.
4.1.4. 9-Methylthio-6-phenyl-6,7,10,12-tetrahydroindeno[1,2-
e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (6)
4.1.8. 9-Methoxy-6-(4-nitrophenyl)-6,7,10,12-tetrahydroin-
deno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (10)
The compound was obtained as a red powder in a yield of 71%;
The compound was obtained as a dark-red powder in a yield of
69%; mp 268–269 °C; FTIR (KBr)
m 3341 (NH); 1613 (C@O); 1582
(C@N and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.42 (s,
;
mp 269 °C; FTIR (KBr)
m
3357 (NH); 1614 (C@O); 1583 (C@N and
3H, SCH3), 5.33 (d, 2H, H-6, J = 4.9 Hz), 7.12 (t, 1H, H-p,
J = 7.9 Hz), 7.17 (d, 2H, H-o, J = 8.5 Hz), 7.25 (d, 2H, H-m,
J = 7.6 Hz), 7.28 (d, 1H, H-4, J = 7.1 Hz), 7.32 (t, 1H, H-3,
J = 6.8 Hz), 7.40 (t, 1H, H-2, J = 7.2 Hz), 7.69 (d, 1H, H-1,
J = 7.3 Hz), 7.70 (d, 1H, H-7, J = 4.6 Hz), 8.74 (s, 1H, H-12), 12.74
(s, 1H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6): d 13.1, 54.4,
101.9, 106.8, 118.0, 120.6, 126.6, 127.0, 128.8, 130.1, 131.5,
134.9, 137.9, 145.4, 148.9, 152.9, 153.9, 160.0, 188.4 ppm. MS
(70 eV) m/z (%): 388 (Mꢀ+, 100), 360 (8), 311 (13), 231 (68). Anal.
Calcd. For C21H16N4O2S: C, 64.93; H, 4.15; N, 14.42; S, 8.25. Found:
C, 64.88; H, 4.19; N, 14.50; S, 8.38.
C@C); 1521, 1340 (NO2) cmꢁ1
;
1H NMR (400 MHz, DMSO-d6): d
3.89 (s, 3H, OCH3), 5.18 (d, 1H, H-6, J = 4.6 Hz), 6.81 (d, 2H, H-o,
J = 8.9 Hz), 7.23 (t, 1H, H-3, J = 7.7 Hz), 7.33 (d, 1H, H-4,
J = 7.4 Hz), 7.40 (t, 1H, H-2, J = 7.9 Hz), 7.64 (d, 2H, H-m,
J = 8.9 Hz), 8.03 (t, 1H, H-1, J = 7.9 Hz), 8.98 (d, 1H, H-7,
J = 4.6 Hz), 10.54 (s, 1H, H-12), 11.67 (s, 1H, H-10) ppm; 13C NMR
(100 MHz, DMSO-d6): d 53.4, 55.3, 98.8, 102.2, 119.7, 119.9,
120.2, 120.4, 124.4, 129.2, 132.8, 134.7, 143.7, 143.8, 144.6,
149.7, 153.6, 156.5, 194.0 ppm. MS (70 eV) m/z (%): 417 (Mꢀ+, 89),
389 (17), 295 (13), 260 (100). Anal. Calcd. For C21H15N5O5: C,
60.43; H, 3.62; N, 16.78. Found: C, 60.39; H, 3.53; N, 16.72.
4.1.5. 9-Methylthio-6-(4-methylphenyl)-6,7,10,12-tetrahydroin-
deno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (7)
The compound was obtained as a dark-red powder in a yield of
4.1.9. 9-Methoxy-6-(4-chlorophenyl)-6,7,10,12-tetrahydroin-
deno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (11)
The compound was obtained as a yellow powder in a yield of
62%; mp 267–268 °C; FTIR (KBr)
m
3340 (NH); 1639 (C@O); 1584
67%; mp 259 °C; FTIR (KBr)
m 3339 (NH); 1621 (C@O); 1587
(C@N and C@C) cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 2.20 (s, 3H,
p-CH3), 2.45 (s, 3H, SCH3), 5.32 (d, 2H, H-6, J = 4.6 Hz), 7.04 (d, 2H,
H-o, J = 8.4 Hz), 7.08 (d, 2H, H-m, J = 8.4 Hz), 7.29 (d, 1H, H-4,
J = 7.0 Hz), 7.33 (t, 1H, H-3, J = 7.3 Hz), 7.41 (t, 1H, H-2, J = 6.8 Hz),
7.63 (d, 1H, H-7, J = 4.8 Hz), 7.73 (d, 1H, H-1, J = 7.3 Hz), 8.74 (s, 1H,
H-12), 12.68 (s, 1H, H-10) ppm; 13C NMR (100 MHz, DMSO-d6): d
12.5, 53.3, 101.2, 106.1, 118.2, 119.9, 126.1, 129.0, 129.6, 130.9,
134.3, 135.67, 137.2, 142.1, 148.5, 152.5, 153.2, 158.5, 187.7 ppm.
MS (70 eV) m/z (%): 402 (Mꢀ+, 100), 374 (11), 311 (19), 245 (72). Anal.
Calcd. For C22H18N4O2S: C, 65.65; H, 4.51; N, 13.92; S, 7.97. Found: C,
65.73; H, 4.44; N, 14.51; S, 7.89.
(C@N and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 3.57 (s,
;
3H, OCH3), 5.32 (d, 1H, H-6, J = 4.6 Hz), 6.82 (d, 2H, H-o,
J = 8.5 Hz), 7.13 (d, 2H, H-m, J = 8.5 Hz), 7.53 (t, 1H, H-3,
J = 7.1 Hz,), 7.61 (d, 1H, H-4, J = 7.7 Hz), 7.70 (t, 1H, H-2,
J = 7.0 Hz), 7.78 (d, 1H, H-7, J = 4.6 Hz), 8.03 (s, 1H, H-12), 8.32 (d,
1H, H-1, J = 7.9 Hz), 12.52 (s, 1H, H-10) ppm; 13C NMR (100 MHz,
DMSO-d6): d 53.4, 54.4, 102.7, 120.4, 120.7, 125.6, 125.9, 130.0,
130.1, 133.3, 138.0, 138.9, 144.2, 146.9, 147.2, 152.8, 156.4,
160.2, 192.3 ppm. MS (70 eV) m/z (%): 406 (Mꢀ+, 100), 378 (6),
295 (19), 250 (89). Anal. Calcd. For C21H15ClN4O3: C, 62.00; H,
3.72; N, 13.77. Found: C, 61.86; H, 3.68; N, 13.81.
4.1.6. 9-Methylthio-6-(4-methoxyphenyl)-6,7,10,12-tetrahydro-
indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (8)
The compound was obtained as a dark-red powder in a yield of
4.1.10. 9-Methoxy-6-(4-bromophenyl)-6,7,10,12-tetrahydroin-
deno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (12)
The compound was obtained as an orange powder in a yield of
65%; mp 295–296 °C; FTIR (KBr)
m
3353 (NH); 1618 (C@O); 1524
63%; mp 264 °C; FTIR (KBr)
m 3341 (NH); 1615 (C@O); 1589 (C@N
(C@N and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.48 (s,
;
and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 3.62 (s, 3H,
;

8498
B. Insuasty et al. / Bioorg. Med. Chem. 16 (2008) 8492–8500
OCH3), 5.29 (d, 1H, H-6, J = 4.6 Hz), 6.75 (d, 2H, H-o, J = 8.5 Hz), 7.27
(d, 2H, H-m, J = 8.5 Hz), 7.53 (t, 1H, H-3, J = 7.0 Hz), 7.60 (d, 1H, H-4,
J = 7.7 Hz), 7.70 (t, 1H, H-2, J = 7.9 Hz), 7.85 (d, 1H, H-7, J = 4.6 Hz),
8.13 (s, 1H, H-12), 8.34 (d, 1H, H-1, J = 7.9 Hz), 12.47 (s, 1H, H-10)
ppm; 13C NMR (100 MHz, DMSO-d6): d 53.3, 54.8, 102.2, 120.7,
121.0, 125.1, 126.1, 130.5, 130.6, 133.3, 134.1, 138.3, 139.0,
146.4, 147.3, 153.2, 156.4, 160.8, 194.9 ppm. MS (70 eV) m/z (%):
450 (Mꢀ+, 94), 422 (9), 296 (17), 293 (100). Anal. Calcd. For
6, J = 4.6 Hz), 7.30 (d, 1H, H-4, J = 7.2 Hz), 7.34 (t, 1H, H-3,
J = 6.8 Hz), 7.42 (t, 1H, H-2, J = 7.2 Hz), 7.44 (d, 2H, H-m,
J = 8.4 Hz), 7.75 (d, 1H, H-1, J = 7.3 Hz), 7.83 (d, 2H, H-o,
J = 8.4 Hz), 7.83 (d, 1H, H-7, J = 5.0 Hz), 8.87 (s, 1H, H-12) ppm;
13C NMR (100 MHz, DMSO-d6): d 14.1, 30.2, 53.0, 100.9, 104.4,
118.5, 120.10, 123.2, 123.9, 127.4, 129.9, 131.2, 134.0, 137.1,
142.7, 146.1, 152.4, 154.8, 158.0, 187.8 ppm. MS (70 eV) m/z (%):
447 (Mꢀ+, 100), 419 (8), 325 (12), 290 (81). Anal. Calcd. For
C21H15BrN4O3: C, 55.89; H, 3.35; N, 12.42. Found: C, 55.76; H,
C22H17N5O4S: C, 59.05; H, 3.83; N, 15.65; S, 7.17. Found: C,
3.28; N, 12.51.
59.13; H, 3.71; N, 15.73; S, 7.09.
4.1.11. 9-Methoxy-6-phenyl-6,7,10,12-tetrahydroindeno[1,2-e]-
pyrimido[4,5-b][1,4]diazepine-5,11-dione (13)
4.1.15. 10-Methyl-9-methylthio-6-(4-chlorophenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (17)
The compound was obtained as an orange powder in a yield of
63%; mp 264 °C; FTIR (KBr)
m
3298 (NH); 1622 (C@O); 1592 (C@N
The compound was obtained as an orange powder in a yield of
and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 3.58 (s, 3H,
;
63%; mp 260–261 °C; FTIR (KBr)
m 3254 (NH), 1670 (C@O), 1580
OCH3), 5.32 (d, 1H, H-6, J = 4.6 Hz), 6.80–7.05 (m, 5H, Aryl), 7.45
(t, 1H, H-3, J = 7.4 Hz), 7.61 (d, 1H, H-4, J = 7.7 Hz), 7.68 (t, 1H, H-
2, J = 7.6 Hz), 7.81 (d, 1H, H-7, J = 4.6 Hz), 8.20 (s, 1H, H-12), 8.31
(d, 1H, H-1, J = 7.9 Hz), 12.39 (s, 1H, H-10) ppm; 13C NMR
(100 MHz, DMSO-d6): d 53.6, 54.4, 101.5, 106.9, 118.2, 120.6,
126.4, 127.3, 129.0, 130.4, 131.5, 134.7, 137.8, 145.1, 148.6,
153.1, 153.8, 160.5, 190.4 ppm. MS (70 eV) m/z (%): 372 (Mꢀ+,
100), 344 (8), 295 (16), 215 (81). Anal. Calcd. For C21H16N4O3: C,
67.73; H, 4.33; N, 15.05. Found: C, 67.66; H, 4.28; N, 15.16.
(C@N and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.49 (s,
;
3H, SCH3), 3.42 (s, 3H, CH3), 5.31 (d, 2H, H-6, J = 4.7 Hz), 7.18 (d,
2H, H-o, J = 8.4 Hz), 7.27 (d, 1H, H-4, J = 7.2 Hz), 7.30 (d, 2H, H-m,
J = 8.4 Hz), 7.32 (t, 1H, H-3, J = 7.3 Hz), 7.40 (t, 1H, H-2,
J = 6.8 Hz), 7.71 (d, 1H, H-1, J = 7.3 Hz), 7.77 (d, 1H, H-7,
J = 4.5 Hz), 9.26 (s, 1H, H-12) ppm; 13C NMR (100 MHz, DMSO-
d6): d 13.5, 54.3, 104.6, 105.8, 118.5, 119.3, 120.8, 127.5, 128.8,
131.0, 132.2, 136.6, 138.5, 146.3, 149.3, 152.3, 155.7, 162.0,
188.8 ppm. MS (70 eV) m/z (%): 436 (Mꢀ+, 100), 408 (10), 325
(16), 279 (79). Anal. Calcd. For C22H17ClN4O2S: C, 60.48; H, 3.92;
N, 12.82; S, 7.34. Found: C, 60.39; H, 3.97; N, 12.77; S, 7.41.
4.1.12. 9-Methoxy-6-(4-methylphenyl)-6,7,10,12-tetrahydroin-
deno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (14)
The compound was obtained as a red powder in a yield of 60%;
4.1.16. 10-Methyl-9-methylthio-6-(4-bromophenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (18)
mp 201 °C; FTIR (KBr)
m 3332 (NH); 1612 (C@O); 1581 (C@N and
C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.20 (s, 3H, p-CH3),
;
3.84 (s, 3H, OCH3), 5.36 (d, 1 H, H-6, J = 4.8 Hz), 7.02 (d, 2H, H-o,
J = 8.0 Hz), 7.10 (d, 2H, H-m, J = 8.3 Hz), 7.18 (d, 1H, H-7,
J = 4.0 Hz), 7.28 (t, 1H, H-2, J = 7.8 Hz), 7.33 (d, 1H, H-4,
J = 7.0 Hz), 7.38 (t, 1H, H-3, J = 7.0 Hz), 7.59 (d, 1H, H-1,
J = 7.3 Hz), 8.38 (s, 1H, H-12), 9.95 (s, 1H, H-10) ppm; 13C NMR
(100 MHz, DMSO-d6): d 20.5, 53.3, 54.4, 99.2, 105.6, 117.9, 119.8,
126.1, 128.9, 129.4, 129.6, 134.1, 134.5, 135.6, 137.1, 142.2,
148.9, 151.6, 152.4, 159.3, 187.3 ppm. MS (70 eV) m/z (%): 386
(Mꢀ+, 92), 358 (10), 295 (21), 229 (91). Anal. Calcd. For
C22H18N4O3: C, 68.38; H, 4.70; N, 14.50. Found: C, 68.29; H, 4.57;
N, 14.60.
The compound was obtained as an orange powder in a yield of
66%; mp 250–251 °C; FTIR (KBr)
m 3268 (NH), 1652 (C@O), 1585
(C@N and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.50 (s,
;
3H, SCH3), 3.44 (s, 3H, CH3), 5.31 (d, 2H, H-6, J = 4.9 Hz), 7.14 (d,
2H, H-o, J = 8.3 Hz), 7.29 (d, 1H, H-4, J = 6.9 Hz), 7.35 (t, 1H, H-3,
J = 7.4 Hz), 7.41 (t, 1H, H-2, J = 7.2 Hz), 7.44 (d, 2H, H-m,
J = 8.3 Hz), 7.69 (d, 1H, H-7, J = 5.0 Hz) 7.74 (d, 1H, H-1, J = 7.3 Hz)
, 8.79 (s, 1H, H-12) ppm; 13C NMR (100 MHz, DMSO-d6): d 14.1,
30.2, 53.0, 100.9, 105.4, 118.3, 119.6, 120.0, 128.4, 130.9, 131.1,
131.3, 134.0, 137.1, 144.3, 146.9, 152.5, 154.6, 157.9, 187.8 ppm.
MS (70 eV) m/z (%): 480 (Mꢀ+, 98), 452 (9), 324 (15), 323 (78). Anal.
Calcd. For C22H17BrN4O2S: C, 54.89; H, 3.56; N, 11.64; S, 6.66.
Found: C, 55.01; H, 3.49; N, 11.60; S, 6.71.
4.1.13. 9-Methoxy-6-(4-methoxyphenyl)-6,7,10,12-tetrahydro-
indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (15)
The compound was obtained as a dark-red powder in a yield of
4.1.17. 10-Methyl-9-methylthio-6-(4-fluorophenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (19)
63%; mp 264 °C; FTIR (KBr)
m 3360 (NH); 1619 (C@O); 1571 (C@N
and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 3.68 (s, 3H, p-
;
OCH3), 3.83 (s, 3H, OCH3), 5.36 (d, 1H, H-6, J = 4.8 Hz), 6.78 (d,
2H, H-o, J = 8.3 Hz), 7.13 (d, 2H, H-m, J = 8.5 Hz), 7.16 (d, 1H, H-7,
J = 4.8 Hz), 7.29 (t, 1H, H-2, J = 7.3 Hz), 7.33 (d, 1H, H-4,
J = 7.0 Hz), 7.39 (t, 1H, H-3, J = 7.3 Hz), 7.59 (d, 1H, H-1,
J = 7.0 Hz), 8.54 (s, 1H, H-12) ppm; 13C NMR (100 MHz, DMSO-
d6): d 53.0, 54.4, 55.0, 99.2, 105.8, 113.8, 114.5, 117.9, 119.9,
127.3, 129.6, 130.8, 134.6, 137.1, 137.2, 149.0, 151.6, 152.5,
157.9, 159.3, 187.4 ppm. MS (70 eV) m/z (%): 402 (Mꢀ+, 89), 374
(7), 295 (17), 245 (88). Anal. Calcd. For C22H18N4O4: C, 65.66; H,
4.51; N, 13.92. Found: C, 65.78; H, 4.48; N, 14.06.
The compound was obtained as a red powder in a yield of 70%;
mp 263–264 °C; FTIR (KBr)
m 3330 (NH), 1680 (C@O), 1563 (C@N
and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.53 (s, 3H,
;
SCH3), 3.43 (s, 3H, CH3), 5.34 (d, 2H, H-6, J = 4.8 Hz), 7.06 (d,
2H, H-o, J = 9.0 Hz), 7.27 (d, 1H, H-4, J = 6.5 Hz), 7.33 (t, 1H, H-3,
J = 7.0 Hz), 7.41 (t, 1H, H-2, J = 7.5 Hz), 7.60 (d, 2H, H-m,
JF = 5.5 Hz, Jo-m = 9.0 Hz), 7.68 (d, 1H, H-1, J = 4.8 Hz), 7.72 (d,
1H, H-7, J = 7.3 Hz), 8.77 (s, 1H, H-12) ppm; 13C NMR (100 MHz,
DMSO-d6): d 14.5, 30.7, 53.3, 101.4, 106.3, 115.6, 115.8, 118.7,
120.5, 128.6, 130.3, 131.6, 134.6, 137.6, 141.6, 147.6, 153.0,
155.1, 158.4, 188.3 ppm. MS (70 eV) m/z (%): 420 (Mꢀ+, 100),
392 (6), 325 (12), 263 (80). Anal. Calcd. For C22H17FN4O2S: C,
62.84; H, 4.08; N, 13.33; S, 7.63. Found: C, 62.80; H, 3.99; N,
13.41; S, 6.58.
4.1.14. 10-Methyl-9-methylthio-6-(4-nitrophenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (16)
The compound was obtained as an orange powder in a yield of
Crystallographic data for 22 were collected at 120 K on a Bruker
63%; mp 269–270 °C; FTIR (KBr)
(C@N and C@C), 1532, 1339 (NO2) cmꢁ1
DMSO-d6): d 2.51 (s, 3H, SCH3), 3.55 (s, 3H, CH3), 5.45 (d, 2H, H-
m
3340 (NH), 1640 (C@O), 1578
Nonius Kappa Roper CCD area diffractometer using Mo-Ka X-ray
radiation (k = 0.71073 ÅA) and deposited at Cambridge Crystallo-
graphic data Center (CCDC reference: 692348).
0
;
1H NMR (400 MHz,

B. Insuasty et al. / Bioorg. Med. Chem. 16 (2008) 8492–8500
8499
4.1.18. 10-methyl-9-methylthio-6-phenyl-6,7,10,12-tetrahydro-
indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (20)
The compound was obtained as an orange powder in a yield of
MS (70 eV) m/z (%): 470 (MÅ+, 100), 442 (5), 325 (12), 313 (90).
Anal. Calcd. For C23H17F3N4O2S: C, 58.72; H, 3.64; N, 11.91; S,
6.82. Found: C, 58.81; H, 3.69; N, 11.86; S, 6.78.
60%; mp 280–281 °C; FTIR (KBr)
m 3345 (NH), 1660 (C@O), 1570
(C@N and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.49 (s,
;
4.1.22. 9-methoxy-10-methyl-6-(4-nitrophenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (24)
3H, SCH3), 3.45 (s, 3H, CH3), 5.33 (d, 2H, H-6, J = 4.8 Hz), 7.13 (t,
2H, H-p, J = 7.9 Hz), 7.21 (t, 2H, H-o, J = 8.5 Hz), 7.38 (d, 2H, H-m,
J = 7.6 Hz), 7.20 (d, 1H, H-7, J = 5.0 Hz), 7.26 (d, 1H, H-4,
J = 7.0 Hz), 7.33 (t, 1H, H-3, J = 6.8 Hz), 7.42 (t, 1H, H-2,
J = 7.2 Hz), 7.70 (d, 1H, H-1, J = 7.3 Hz), 8.74 (s, 1H, H-12) ppm;
13C NMR (100 MHz, DMSO-d6): d 14.5, 30.7, 54.0, 100.0, 106.5,
118.6, 120.5, 126.7, 127.1, 129.0, 130.3, 131.6, 134.6, 137.7,
145.5, 147.6, 153.0, 155.0, 158.4, 184.6 ppm. MS (70 eV) m/z (%):
402 (Mꢀ+, 100), 374 (11), 325 (21), 245 (91). Anal. Calcd. For
The compound was obtained as a red powder in a yield of 86%;
mp 262 °C; FTIR (KBr)
m
3381 (NH), 1648 (C@O), 1570 (C@N and
C@C), 1531, 1338 (NO2) cmꢁ1
;
1H NMR (400 MHz, DMSO-d6): d
3.34 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 5.43 (d, 2H, H-6, J = 4.8 Hz),
7.30 (d, 1H, H-4, J = 6.8 Hz), 7.35 (t, 1H, H-3, J = 7.0 Hz), 7.43 (t,
1H, H-2, J = 7.4 Hz), 7.45 (d, 2H, H-o, J = 8.9 Hz), 7.74 (d, 1H, H-1,
J = 7.2 Hz), 7.77 (d, 1H, H-7, J = 4.8 Hz), 8.12 (d, 2H, H-m,
J = 8.9 Hz), 8.83 (s, 1H, H-12) ppm; 13C NMR (100 MHz, DMSO-
d6): d 27.9, 53.0, 55.4, 99.1, 103.9, 118.3, 120.0, 123.8, 127.3,
129.8, 131.0, 134.2, 137.0, 146.0, 147.0, 150.9, 152.6, 156.7,
158.6, 187.5 ppm. MS (70 eV) m/z (%): 431 (Mꢀ+, 5), 403 (11), 303
(60), 181 (60), 155 (100). Anal. Calcd. For C22H17N5O5: C, 61.25;
H, 3.97; N, 16.23. Found: C, 61.16; H, 4.03; N, 16.11.
C22H18N4O2S: C, 65.65; H, 4.51; N, 13.92; S, 7.97. Found: C,
65.71; H, 4.43; N, 14.00; S, 7.81.
4.1.19. 10-methyl-9-methylthio-6-(4-methylphenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (21)
The compound was obtained as an orange powder in a yield of
61%; mp 255–256 °C; FTIR (KBr)
m
3360 (NH), 1635 (C@O), 1568
4.1.23. 9-methoxy-10-methyl-6-(4-chlorophenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (25)
(C@N and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.10 (s,
;
3H, p-CH3), 2.49 (s, 3H, SCH3), 3.43 (s, 3H, CH3), 5.30 (d, 2H, H-6,
J = 4.8 Hz), 6.79 (d, 2H, H-o, J = 8.8 Hz), 7.09 (d, 2H, H-m,
J = 8.8 Hz), 7.27 (d, 1H, H-4, J = 6.8 Hz), 7.33 (t, 1H, H-3,
J = 7.0 Hz), 7.41 (t, 1H, H-2, J = 7.3 Hz), 7.71 (d, 1H, H-1,
J = 4.8 Hz), 7.71 (d, 1H, H-7, J = 7.3 Hz), 8.72 (s, 1H, H-12) ppm;
13C NMR (100 MHz, DMSO-d6): d 14.5, 20.9, 30.7, 53.8, 101.6,
107.17, 114.5, 117.9, 120.6, 127.8, 130.1, 131.1, 134.8, 137.4,
138.9, 147.6, 152.9, 155.0, 158.6, 188.5 ppm. MS (70 eV) m/z (%):
416 (Mꢀ+, 100), 388 (7), 325 (13), 259 (78). Anal. Calcd. For
The compound was obtained as an orange powder in a yield of
72%; mp 267–268 °C; FTIR (KBr)
m 3340 (NH), 1636 (C@O), 1585
(C@N and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 3.28 (s,
;
3H, CH3), 3.86 (s, 3H, OCH3), 5.30 (d, 2H, H-6, J = 4.8 Hz), 7.18 (d,
2H, H-o, J = 8.5 Hz), 7.26 (d, 1H, H-4, J = 5.5 Hz), 7.28 (d, 2H, H-m,
J = 8.0 Hz), 7.32 (t, 1H, H-3, J = 7.5 Hz), 7.39 (t, 1H, H-2,
J = 7.5 Hz), 7.61 (d, 1H, H-7, J = 4.5 Hz), 7.68 (d, 1H, H-1,
J = 7.0 Hz), 8.69 (s, 1H, H-12) ppm; 13C NMR (100 MHz, DMSO-
d6): d 28.4, 53.6, 55.9, 99.9, 105.6, 118.2, 120.5, 128.5, 128.8,
130.2, 131.4, 131.7, 134.9, 137.7, 144.4, 147.7, 151.4, 153.0,
159.2, 188.1 ppm. MS (70 eV) m/z (%): 420 (Mꢀ+, 60), 392 (9), 309
(12), 292 (100), 281 (53), 263 (58). Anal. Calcd. For C22H17ClN4O3:
C, 62.79; H, 4.07; N, 13.31. Found: C, 62.83; H, 3.95; N, 13.26.
C23H20N4O2S: C, 66.33; H, 4.84; N, 13.45; S, 7.70. Found: C,
66.41; H, 4.76; N, 13.52; S, 7.63.
4.1.20. 10-methyl-9-methylthio-6-(4-methoxyphenyl)-6,7,10,-
12-tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (22)
The compound was obtained as a red powder in a yield of 63%;
4.1.24. 9-methoxy-10-methyl-6-(4-bromophenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (26)
mp 280–281 °C; FTIR (KBr)
m 3210 (NH), 1690 (C@O), 1559 (C@N
and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.51 (s, 3H,
;
SCH3), 3.44 (s, 3H, CH3), 3.50 (s, 3H, p-OCH3), 5.28 (d, 2H, H-6,
J = 4.5 Hz), 6.77 (d, 2H, H-o, J = 8.8 Hz), 7.12 (d, 2H, H-m,
J = 8.5 Hz), 7.23 (d, 1H, H-7, J = 6.5 Hz), 7.29 (d, 1H, H-4,
J = 7.0 Hz), 7.33 (t, 1H, H-3, J = 7.4 Hz), 7.41 (t, 1H, H-2,
J = 4.8 Hz), 7.60 (d, 1H, H-1, J = 7.3 Hz), 8.47 (s, 1H, H-12) ppm;
13C NMR (100 MHz, DMSO-d6): d 14.5, 30.7, 53.3, 55.7, 101.4,
106.3, 115.6, 118.7, 120.5, 128.6, 130.2, 131.2, 134.6, 137.6,
141.6, 147.6, 153.0, 155.1, 158.4, 188.3 ppm. MS (70 eV) m/z (%):
432 (Mꢀ+, 100), 404 (8), 325 (11), 275 (62). Anal. Calcd. For
The compound was obtained as an orange powder in a yield of
64%; mp 272 °C; FTIR (KBr)
m 3341 (NH), 1634 (C@O), 1588 (C@N
and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 3.32 (s, 3H,
;
CH3), 3.90 (s, 3H, OCH3), 5.30 (d, 2H, H-6, J = 4.6 Hz), 7.14 (d, 2H,
H-o, J = 8.5 Hz), 7.28 (d, 1H, H-4, J = 6.9 Hz), 7.35 (t, 1H, H-3,
J = 7.2 Hz), 7.43 (t, 1H, H-2, J = 7.6 Hz), 7.44 (d, 2H, H-m,
J = 8.5 Hz), 7.62 (d, 1H, H-7, J = 4.8 Hz) 7.73 (d, 1H, H-1,
J = 7.2 Hz) , 8.74 (s, 1H, H-12) ppm; 13C NMR (100 MHz, DMSO-
d6): d 27.9, 53.0, 55.4, 99.1, 104.8, 118.2, 119.6, 119.9, 128.4,
129.8, 131.0, 131.3, 134.3, 137.0, 144.5, 147.2, 150.9, 152.6,
158.5, 187.4 ppm. MS (70 eV) m/z (%): 464 (Mꢀ+, 92), 449 (17),
436 (4), 309 (80), 281 (24). Anal. Calcd. For C22H17BrN4O3: C,
56.79; H, 3.68; N, 12.04; S, 6.66. Found: C, 56.82; H, 3.55; N, 11.94.
C23H20N4O3S: C, 63.87; H, 4.66; N, 12.95; S, 7.41. Found: C,
63.79; H, 4.71; N, 12.92; S, 7.33.
4.1.21. 10-methyl-9-methylthio-6-(4-trifluoromethylphenyl)-
6,7,10,12-tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-
5,-11-dione (23)
4.1.25. 9-methoxy-10-methyl-6-phenyl-6,7,10,12-tetrahydroin-
deno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-dione (27a)
The compound was obtained as an orange powder in a yield of
The compound was obtained as an orange powder in a yield of
69%; mp 284–285 °C; FTIR (KBr)
m 3232 (NH), 1658 (C@O), 1559
(C@N and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.47 (s,
;
67%; mp 265 °C; FTIR (KBr)
m 3340 (NH), 1630 (C@O), 1579 (C@N
3H, SCH3), 3.50 (s, 3H, CH3), 5.70 (d, 2H, H-6, J = 4.6 Hz), 7.34 (d,
2H, H-o, J = 8.3 Hz), 7.29 (d, 1H, H-4, J = 6.8 Hz), 7.30 (t, 1H, H-3,
J = 7.3 Hz), 7.40 (d, 2H, H-m, J = 8.4 Hz), 7.39 (t, 1H, H-2,
J = 7.0 Hz), 7.60 (d, 1H, H-1, J = 4.7 Hz), 7.74 (d, 1H, H-7,
J = 7.3 Hz), 8.88 (s, 1H, H-12) ppm; 13C NMR (100 MHz, DMSO-
d6): d 13.3, 55.6, 102.9, 104.9, 119.2, 122.6, 127.8, 129.6, 132.2,
133.5, 135.0, 137.9, 148.7, 152.0, 152.9, 155.2, 160.2, 188.7 ppm.
and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 3.32 (s, 3H,
;
CH3), 3.91 (s, 3H, OCH3), 5.40 (d, 2H, H-6, J = 4.8 Hz), 7.18–7.22
(m, 5H, Aryl), 7.28 (d, 1H, H-4, J = 6.8 Hz), 7.32 (t, 1H, H-3,
J = 7.3 Hz), 7.40 (t, 1H, H-2, J = 7.3 Hz), 7.59 (d, 1H, H-1,
J = 7.3 Hz), 7.93 (d, 1H, H-7, J = 4.8 Hz), 8.45 (s, 1H, H-12) ppm;
13C NMR (100 MHz, DMSO-d6): d 27.7, 53.7, 55.1, 99.3, 105.5,
117.1, 119.8, 125.9, 126.3, 128.1, 129.4, 130.7, 134.3, 137.1,

8500
B. Insuasty et al. / Bioorg. Med. Chem. 16 (2008) 8492–8500
144.8, 147.2, 150.7, 152.2, 158.6, 187.6 ppm. MS (70 eV) m/z (%):
386 (Mꢀ+, 39), 358 (8), 309 (13), 281 (5), 258 (9), 229 (100). Anal.
Calcd. For C22H18N4O3: C, 68.38; H, 4.70; N, 14.50. Found: C,
68.30; H, 4.81; N, 14.62.
J = 4.8 Hz), 7.66 (d, 1H, H-1, J = 7.3 Hz), 8.60 (s, 1H, H-12) ppm;
13C NMR (100 MHz, DMSO-d6): d 28.3, 53.8, 55.7, 55.8, 99.7,
106.6, 114.5, 117.8, 120.4, 127.8, 130.1, 131.3, 135.0, 137.7,
137.9, 147.9, 151.3, 152.9, 158.7, 159.2, 186.3, 188.1 ppm. MS
(70 eV) m/z (%): 416 (Mꢀ+, 79), 388 (8), 309 (5), 288 (100), 281
(35), 259 (62). Anal. Calcd. For C23H20N4O4: C, 66.34; H, 4.84; N,
13.45. Found: C, 66.23; H, 4.90; N, 13.58.
4.1.26. 5a-hydroxy-9-methoxy-10-methyl-6-phenyl-5a,6,7,10-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (27b)
The compound was obtained as orange crystals in a yield of
Acknowledgments
25%; mp 255 °C; FTIR (KBr)
m
3352–3338 (NH and OH), 1682
(C@O), 1579 (C@N and C@C) cmꢁ1
;
1H NMR (400 MHz, DMSO-
The authors wish to credit The Developmental Therapeutics
Program (DTP) of the National Cancer Institute of the United States
(U.S.) for performing the screening of compounds. This work was
financially supported by Colciencias, Universidad del Valle, Conse-
jería de Innovación, Ciencia y Empresa (Junta de Andalucía, Spain)
and the Universidad de Jaén. Authors thank ‘‘Servicios Técnicos de
Investigación of Universidad de Jaén” and the staff for spectro-
scopic data collection, and the UK Engineering and Physical Sci-
ences Research Council for support of the X-ray diffraction
facilities at Southampton. Fabián Orozco thanks Colciencias for
his fellowship.
d6): d 3.32 (s, 3H, CH3), 3.96 (s, 3H, OCH3), 4.99 (d, 2H, H-6,
J = 6.6 Hz), 6.49 (s, 1H, 5a-OH), 6.83 (d, 2H, H-o, J = 7.0 Hz), 6.98–
7.07 (m, 3H, H-m and H-p), 7.39 (t, 1H, H-3, J = 7.9 Hz), 7.52 (d,
1H, H-4, J = 7.7 Hz), 7.63 (t, 1H, H-2, J = 7.9 Hz), 7.74 (d, 1H, H-1,
J = 7.9 Hz), 8.16 (d, 1H, H-7, J = 6.6 Hz) ppm; 13C NMR (100 MHz,
DMSO-d6): d 27.6, 55.3, 62.4, 76.7, 106.1, 121.1, 122.8, 126.9,
127.3, 127.9, 129.2, 130.5, 135.4, 136.2, 139.7, 147.7, 152.4,
153.0, 161.0, 200.9 ppm. MS (70 eV) m/z (%): 420 (Mꢀ+, 11), 402
(11), 374 (39), 357 (16), 297 (90), 242 (62), 72 (100). Anal. Calcd.
For C22H18N4O4.H2O: C, 62.85; H, 4.79; N, 13.33. Found: C, 62.77;
H, 4.86; N, 13.25.
Crystallographic data for 27b were collected at 120 K on a Bru-
References and notes
ker Nonius Kappa Roper C0CD area diffractometer using Mo-K
ray radiation (k = 0.71073 ÅA) and deposited at Cambridge Crystallo-
graphic data Center (CCDC reference: 692349).
a X-
1. Landquist, J. K. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W. (Eds.); Pergamon: Oxford, 1984; p 166.
2. Schutz, H. Benzodiazepines; Springer: Heidelberg, 1982.
3. Insuasty, B.; Ramos, M.; Quiroga, J.; Sánchez, A.; Nogueras, M.; Hanold, N.;
Meier, H. J. Heterocycl. Chem. 1994, 31, 61–64.
4. Insuasty, B.; Ramos, M.; Moreno, R.; Quiroga, J.; Sánchez, A.; Nogueras, M.;
Hanold, N.; Meier, M. J. Heterocycl. Chem. 1995, 32, 1229–1233.
5. Insuasty, B.; Perez, A.; Valencia, J.; Quiroga, J. J. Heterocycl. Chem. 1997, 34,
1555.
6. Insuasty, B.; Orozco, F.; Quiroga, J.; Abonía, R.; Nogueras, M.; Cobo, J. Eur. J. Med.
Chem. 2008. doi:10.1016/j.ejmech.2007.12.005.
7. Nishiyama, T.; Shiotsu, S.; Tsujita, H. Poly. Deg. Stab. 2002, 76, 435.
8. Murdock, K. C. J. Org. Chem. 1959, 24, 845.
9. Khordorkovsky, V.; Mazor, R. A.; Ellern, A. Acta Crystallogr. 1996, C52, 2878.
10. Schwartz, H.; Mazor, R.; Khordorkovsky, V.; Shapiro, L.; Klug, J. T.; Kovalev, E.;
Meshulum, G.; Berkovic, G.; Kotler, Z.; Efrima, S. J. Phys. Chem. 2001, 105, 5914.
11. Ramachary, D.; Anebouselvy, K.; Chowdary, N.; Barbas, C. J. Org. Chem. 2004, 40,
20.
12. Salama, M.; Yousif, N.; Ahmed, F.; Hamman, A. Pol. J. Chem. 1998, 62, 43.
13. Nugiel, D.; Etzkorn, A.; Vidwans, A.; Benfield, P.; Bosclair, M.; Burton, C.; Cox,
S.; Czerniak, M.; Doleniak, D.; Seitz, S. J. Med. Chem. 2001, 44, 1334.
14. Nugiel, D.; Vidwans, A.; Etzkorn, A.; Rossi, K.; Benfield, P.; Burton, C.; Cox, S.;
Czerniak, M.; Doleniak, D.; Seitz, S. J. Med. Chem. 2002, 45, 5224.
15. Wang, H.; Zhou, X.; Xu, J.; Jin, S.; Li, Y.; Chan, A. S. C. J. Heterocycl. Chem. 2001,
38, 1031–1034.
4.1.27. 9-Methoxy-10-methyl-6-(4-methylphenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (28)
The compound was obtained as a red powder in a yield of 58%;
mp 257 °C; FTIR (KBr)
m 3335 (NH), 1635 (C@O), 1584 (C@N and
C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.18 (s, 3H, p-CH3),
;
3.32 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 5.36 (d, 2H, H-6, J = 4.8 Hz),
7.00 (d, 2H, H-o, J = 8.0 Hz), 7.09 (d, 2H, H-m, J = 7.8 Hz), 7.13 (d,
1H, H-7, J = 4.5 Hz), 7.29 (t, 1H, H-3, J = 7.0 Hz), 7.33 (d, 1H, H-4,
J = 7.0 Hz), 7.40 (t, 1H, H-2, J = 7.3 Hz), 7.58 (d, 1H, H-1,
J = 7.3 Hz), 8.42 (s, 1H, H-12) ppm; 13C NMR (100 MHz, DMSO-
d6): d 20.0, 27.6, 53.3, 55.0, 99.0, 99.2, 105.7, 117.0, 119.7, 125.8,
128.6, 129.3, 130.6, 134.3, 135.4, 141.7, 147.1, 150.6, 152.1,
158.5, 187.4 ppm. MS (70 eV) m/z (%): 400 (Mꢀ+, 98), 372 (7), 309
(20), 272 (100), 243 (70). Anal. Calcd. For C23H20N4O3: C, 68.99;
H, 5.03; N, 13.99. Found: C, 69.08; H, 4.89; N, 14.10.
16. Syollosy, A.; Kotorych, G. Can. J. Chem. 1988, 66, 279.
17. Azizian, J.; Karimi, A. R.; Kazemizadeh, Z.; Mohammadi, A. A.;
Mohammadizadeh, M. R. J. Org. Chem. 2005, 70, 1471–1473.
18. Kidwai, M.; Mothsra, P. Synth. Commun. 2006, 36, 817–824.
19. Quiroga, J.; Insuasty, B.; Gallo, G. Bol. Soc. Chil. Quím. 1996, 41, 415–421.
20. Boyd, M. R. Am. Soc. Cancer. Res. 1989, 30, 652–663.
21. Monks, A. P.; Scudiero, D. A.; Skehan, P.; Shoemaker, R. H.; Paull, K. D.; Vistica,
C.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Gray-Goodrich, M.;
Campbell, H.; Mayo, M.; Boyd, M. J. Natl. Cancer Inst. 1991, 83, 757–766.
22. Weinstein, J. N.; Myers, T. G.; O’Connor, P. M.; Friend, S. H., Jr.; Fornace, A. J.;
Kohn, K. W.; Fojo, T.; Bates, S. E.; Rubinstein, L. V.; Anderson, N. L.; Buolanwini,
J. K.; van Osdol, W. W.; Monks, A. P.; Scudiero, D. A.; Sausiville, E. A.; Zaharevitz,
D. W.; Bunow, B.; Viswanadhan, V. N.; Jhonson, G. S.; Wittes, R. E.; Paull, K. D.
Science 1997, 275, 343–349.
4.1.28. 9-Methoxy-10-methyl-6-(4-methoxyphenyl)-6,7,10,12-
tetrahydroindeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-
dione (29)
The compound was obtained as a red powder in a yield of 55%;
mp 270–271 °C; FTIR (KBr)
m 3338 (NH), 1642 (C@O), 1580 (C@N
and C@C) cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 3.28 (s, 3H,
;
CH3), 3.63 (s, 3H, p-OCH3), 3.86 (s, 3H, OCH3), 5.27 (d, 2H, H-6,
J = 4.8 Hz), 6.77 (d, 2H, H-o, J = 8.5 Hz), 7.09 (d, 2H, H-m,
J = 8.5 Hz), 7.26 (d, 1H, H-4, J = 6.8 Hz), 7.32 (t, 1H, H-3,
J = 7.3 Hz), 7.39 (t, 1H, H-2, J = 7.5 Hz), 7.50 (d, 1H, H-7,